Biology subjects

Dahary, D.

Publications and source records attributed to Dahary, D..

5 recordsLinked to original sources

bioRxiv2026

Evolution of a genome-architecture-encoded gene regulation system in trypanosomatids

Transcriptional regulation of protein-coding genes is a hallmark of eukaryotic gene expression. Yet, a group of parasitic protists, trypanosomatids, appear to lack this capability. Here, we analyzed genomic, nascent transcriptomic, RNA polymerase occupancy and gene organization data to reconstruct the evolutionary origin and biological consequences of their unusual regulatory strategy. Across 59 Discoba protists, we show stepwise evolutionary erosion of conventional transcription regulation components in trypanosomatida lineage, including gene consolidation into polycistronic transcription units (PTUs), shortening of intra-PTU non-coding regions, and depletion of transcription factors and their enriched DNA-binding motifs. This transition was associated with near-constitutive expression of most genes, indicating broad loss of conditional gene expression. However, trypanosomatids retain some differential regulation at the PTU level, with >70% PTUs featuring significantly different nascent transcription than their neighbors or resident chromosomes. Moreover, gene expression is not uniform within PTUs: nascent transcription, translation efficiency, and protein abundance progressively decline with distance from the transcription start site. Consistent with this architecture-encoded regulatory logic, co-complex subunits and co-pathway enzymes preferentially occupy adjacent positions within PTUs despite each PTUs overall functional heterogeneity. These findings reveal an evolutionary shift from gene-specific transcriptional regulation toward a regime where genome architecture becomes a regulator of gene expression.

evolutionary biology↗

bioRxiv2026

An information content principle explains regulatory patterns of gene expression across human tissues

Gene expression patterns range from broadly expressed housekeeping genes to highly tissue-specific ones. Notably, many genes exhibit intermediate specificity, characterized by elevated expression in some tissues while low or absent in others. Understanding how regulatory demands scale with tissue specificity offers a valuable opportunity to uncover fundamental principles of genome regulation. By analyzing cis-regulatory element (CRE) counts across human genes with varying tissue specificity, we observed a nonlinear pattern: genes with intermediate specificity harbor the highest CRE count, suggesting distinct regulatory strategies across the expression spectrum. Motivated by this observation, we used the Minimum Description Length (MDL) principle from information theory, together with a maximum parsimony approach from phylogenetics, to quantify regulatory demands across tissues. Our analysis revealed that MDL-based regulatory demand scales consistently with diverse regulatory features, including CRE count, transcription-factor and microRNA targeting, and gene structure. To test whether this scaling changes across the expression spectrum, we partitioned genes by expression breadth. Two patterns emerged: features scaling with MDL in selectively expressed genes tend to act as on/off switches, whereas those in ubiquitous genes serve as fine-tuning knobs. Evolutionary analysis revealed that these regulatory patterns vary with gene age, with alignment between MDL and CRE counts peaking in intermediate-aged genes. Collectively, these results establish MDL combined with maximum parsimony as a powerful framework linking regulatory architecture, expression specificity, and evolutionary age, offering novel insights into the organizational principles underlying genome regulation.

genomics↗

bioRxiv2025

The evolutionary origin of host association and polycistronic transcription in trypanosomatids

Trypanosomatids (Kinetoplastids) encompass multiple lineages of parasitic protists with monoxenous or dixenous life cycles, infecting insects, vertebrates, and plants; in vertebrate hosts, some are intracellular, while others are extracellular. To understand the origin and diversification of their host associations, we integrated comparative genomics across 47 genomes. Results highlight that monoxenous, extracellular trypanosomatids originated from predatory ancestors through reductive evolution, which diminished their metabolic and hunting capabilities. Intracellularity and dixenous lifestyle convergently originated three times independently. Progressive consolidation of genes into polycistronic transcription units (PTUs) was a central innovation that began in early Glycomonada and expanded through chromosome fission-fusion and gene relocation/inversion. In present-day PTUs, protein complex subunits and metabolic pathway enzymes are positioned for co-expression in temporal synchrony, and chromosomes minimize colinear PTUs to counter transcriptional readthrough. Together, these results provide a time-resolved origin of host-association and polycistronic transcription in trypanosomatids, possibly through an intermediate phase of facultative parasitism.

evolutionary biology↗

bioRxiv2025

Encoded and non-genetic alternative protein variants expand human functional proteome

Each stage of the Central Dogma contributes to proteome diversity through mechanisms such as heterozygosity, somatic mutations, transcriptional errors, and translational errors. As a result, a diverse array of protein variants can coexist within a single proteome, such as that of humans. However, until now, methods to detect, quantify, and evaluate the functional consequences of these variants have been lacking. Here we examined a large-scale proteogenomic dataset from 29 healthy human tissues and uncovered 13,910 confidently localized variants representing 7,215 unique single amino acid substitutions co-existing alongside their corresponding reference proteoforms. We found that the abundance of both genetic (SNPs, somatic mutations) and mistranslated protein variants mirrors their allele frequencies in the human population. Moreover, we show that non-genetic substitutions may provide a distinct route for exploring protein sequence space, circumventing the mutational constraints imposed by the genetic code. In addition, we provide experimental validation of non-genetic substitution on selected purified proteins. We demonstrate specific and recurring non-genetic variation patterns upon amino acid starvation in proteome-wide analyses of cancer-derived cell lines and identify hundreds of substituted non-genetic proteoforms that recur consistently in multiple healthy individuals or map to annotated protein functional sites. We propose that these substitutions constitute a novel class of functional protein phenotypic variants. Collectively, our findings indicate that non-genetic amino acid substitutions in human proteins provide an abundant source to expanding the functional proteome.

molecular biology↗

bioRxiv2018

Identification of a secretion-enhancing cis regulatory targeting element (SECReTE) involved in mRNA localization and protein synthesis

Earlier dogma states that mRNAs encoding secreted and membrane protein (mSMPs) reach the ER in a translation-dependent manner through the signal recognition particle (SRP) pathway. In this pathway, the signal sequence of the translation product is recognized by SRP and the mRNA-ribosome-nascent-chain-SRP complex is recruited to the ER via the interaction with an endoplasmic reticulum (ER)-localized SRP receptor. This model suggests that the translation product dictates the delivery of mRNAs to the ER and that the mRNA is a passive passenger. However, new evidence challenges this model and implies the existence of both translation - and SRP-independent mRNA localization to the ER, raising the possibility that mRNAs have an active role in determining their localization to the ER.\n\nBesides serving as a template for protein translation, mRNAs carry information required for other regulatory processes such as mRNA processing, translation and transcription efficiency, degradation and localization. In yeast, mRNA localization governed by cis-acting sequence elements has been characterized for asymmetrically (e.g. bud) localized mRNAs that localize to, and are transported with, cortical ER. Now, we identify a cis motif in mSMPs that targets mRNAs mainly to the nuclear ER in yeast and increases both protein synthesis and secretion. Termed SECReTE, for secretion-enhancing cis regulatory targeting element, this motif was identified by computational analysis of genes encoding secretome proteins. SECReTE consists of [≥]10 repetitive triplets enriched with pyrimidines (i.e. Cs and Us) every third base (i.e. NNY, N - any nucleotide, Y - pyrimidine), and is found particularly in mRNAs coding for cell wall proteins. To study the physiological relevance of SECReTE, we introduced synonymous mutations that either elevate or decrease its overall score in genes coding for secreted proteins, without changing the protein sequence, and examined the physiological effects in yeast. An increase in the SECReTE score elevated the synthesis and secretion of endogenous proteins while, in contrast, a reduction led to less secretion and physiological defects. Importantly, the addition of SECReTE to the 3UTR of an exogenous protein (e.g. SS-GFP) led to its increased secretion from yeast. SECReTE is present all through evolution and, thus, constitutes a novel RNA targeting motif found in both prokaryotes and eukaryotes.

cell biology↗